Primary liver cancer is the third most common cause of cancer-related death worldwide. Estimates predict that death from this disease is on the rise because both incidence and mortality are projected to increase. Death usually follows organ failure from progression of local disease. Often patients have already progressed to advanced and unresectable tumors at the time the disease is diagnosed, largely because early stage disease exhibits no symptoms. In such cases, only non-surgical palliative treatment options are available. Image- guided interventions have emerged as potent minimally invasive procedures that offer individualized tumor targeting, with ability to address local disease and minimize systemic toxicities. Yet, these procedures only modestly improve patient survival, creating a need for new technology. The effectiveness of non-ablative heat therapy or hyperthermia (HT) as a complement for other therapies is well-established for unresectable cancers. HT broadly affects tumor biology and it can dramatically affect tumor structure and physiology in ways that enhance the potency of chemotherapeutic agents. The critical barriers to effectively implementing HT for cancer therapy have been targeting the heat to the tumor and delivering the proper heat dose. Magnetic iron oxide nanoparticles (MIONs) offer the capability to overcome these barriers because they provide both heating and imaging capability to enhance targeted delivery of therapy. MIONs produce heat within the tumor when exposed to alternating magnetic fields (AMFs). This heat conducts throughout the tumor to enhance delivery and effectiveness of other therapeutic agents. An image-guided approach offers the potential of real-time visualization of MION distribution with feedback on effective tumor targeting and the necessary information to develop robust treatment planning, creating the potential for individualized therapy. We have recently developed a MION formulation that provides dual imaging (x-ray and magnetic resonance), heating with low- power magnetic fields, and that enables co-formulation with standard chemotherapy agents. This formulation comprises MIONs, embedded in the oily medium of lipiodol. We hypothesize that x-ray image-guided magnetic hyperthermia will sensitize cancer cells to chemotherapy leading to superior efficacy when compared to chemotherapy alone. The effects of therapy, following image-guided delivery of the MION-lipiodol formulation will be assessed in xenograft mouse models of hepatocellular carcinoma. Imaging and image-guided delivery, biodistribution of MIONs, and quantitative measures of MION distribution before and after heating will be assessed in the orthotopic VX2 tumor model in rabbit livers, a preferred animal model for interventional image- guided liver procedures. Successful completion of the proposed project will provide the necessary data and tools to advance this technology closer to clinical treatment of unresectable primary liver cancer.